Rigorous testing of the efficacy of dietary patterns and nutritional components in colon cancer prevention in humans has been extremely limited by practical constraints. Using colonic neoplasms as endpoints in clinical trials requires extremely large sample sizes, prolonged follow-up, or both. In addition, maintaining prolonged complex dietary interventions in clinical trials is difficult. Animal experimental evidence and exciting preliminary evidence in humans strongly suggests that hyperproliferation of colonic crypt epithelial cells is a biomarker or precursor lesion for colonic neoplasia and that this hyperproliferation can be reversed by nutritional intervention and the risk of colonic cancer thereby reduced. Limited flawed information is available regarding the relation of colonic epithelial cell proliferation (CECP) to colonic neoplasia in humans and is restricted to CECP measurement using tritiated thymidine labeling of S-phase cells. This procedure and its unvalidated successor, 5-bromodeoxyuridine (BrdU) labeling of S-phase cells, are not feasible for use in full-scale human intervention trials. We have now adapted the more reliable and feasible proliferating cell nuclear antigen (PCNA) and whole crypt mitotic count (WCMC) techniques of measuring CECP. Since earlier validation studies used a technique not suitable for large scale clinical trials and were, as we now know, inadequate studies on which to justify large scale clinical trials, we propose to evaluate more properly the relationship of CECP to risk of colon neoplasia in humans and to do so using the newer techniques (PCNA and WCMC). We propose to do this by the financially and technically efficient expedient of extending and modifying our current case-control study of colonic polyps. In the current case-control study, patients going to colonoscopy complete questionnaires on colon cancer risk factors such as diet, nutritional supplement intake, family history, etc. Patients also have blood drawn for lipid profiles and DNA for acetyltransferase and APC genotypes. Incident adenoma patients are cases, and patients with normal colonoscopies and without a history of colonic neoplasms are controls. We propose to obtain rectal, sigmoid, and proximal colon mucosal biopsies at these usual-care colonoscopies and from these determine CECP by both the PCNA and WCMC techniques. From this information, we will establish interrelationships among colon neoplasia risk factors (especially dietary), CECP, and colon neoplasia; whether or not CECP levels measured on a rectal biopsy reflects levels throughout the colon; whether CECP measured by the PCNA or the WCMC techniques or a combination of the two provides greater discriminatory power in distinguishing levels and causes of increased risk of neoplasia; and whether the PCNA or the WCMC technique is more reliable and/or feasible for application to full-scale dietary/chemoprevention trials.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA066539-02
Application #
2109932
Study Section
Special Emphasis Panel (SRC (70))
Project Start
1994-09-15
Project End
1997-08-31
Budget Start
1995-09-01
Budget End
1996-08-31
Support Year
2
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
041418799
City
Winston-Salem
State
NC
Country
United States
Zip Code
27106
Yin, Xin; Bostick, Roberd M (2018) Associations of Nut Intakes with Incident Sporadic Colorectal Adenoma: A Pooled Case-Control Study. Nutr Cancer :1-8
Mujtaba, Sobia; Bostick, Roberd M (2018) Differences in risk factor-colorectal adenoma associations according to non-steroidal anti-inflammatory drug use. Eur J Gastroenterol Hepatol 30:1318-1326
Thyagarajan, Bharat; Guan, Weihua; Fedirko, Veronika et al. (2018) Associations of mitochondrial polymorphisms with sporadic colorectal adenoma. Mol Carcinog 57:598-605
Gibbs, David C; Fedirko, Veronika; Um, Caroline et al. (2018) Associations of Circulating 25-Hydroxyvitamin D3 Concentrations With Incident, Sporadic Colorectal Adenoma Risk According to Common Vitamin D-Binding Protein Isoforms. Am J Epidemiol 187:1923-1930
Um, Caroline Y; Fedirko, Veronika; Flanders, W Dana et al. (2017) Associations of Calcium and Milk Product Intakes with Incident, Sporadic Colorectal Adenomas. Nutr Cancer 69:416-427
Thyagarajan, Bharat; Guan, Weihua; Fedirko, Veronika et al. (2016) No association between mitochondrial DNA copy number and colorectal adenomas. Mol Carcinog 55:1290-6
Bostick, Roberd M (2015) Effects of supplemental vitamin D and calcium on normal colon tissue and circulating biomarkers of risk for colorectal neoplasms. J Steroid Biochem Mol Biol 148:86-95
Yang, Baiyu; Thyagarajan, Bharat; Gross, Myron D et al. (2014) No evidence that associations of incident, sporadic colorectal adenoma with its major modifiable risk factors differ by chromosome 8q24 region rs6983267 genotype. Mol Carcinog 53 Suppl 1:E193-200
Kong, So Yeon J; Bostick, Roberd M; Flanders, W Dana et al. (2014) Oxidative balance score, colorectal adenoma, and markers of oxidative stress and inflammation. Cancer Epidemiol Biomarkers Prev 23:545-54
Yang, Baiyu; Thyagarajan, Bharat; Gross, Myron D et al. (2014) Genetic variants at chromosome 8q24, colorectal epithelial cell proliferation, and risk for incident, sporadic colorectal adenomas. Mol Carcinog 53 Suppl 1:E187-92

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